Nerve growth factor (NGF) was the first recognized and is now one of the best characterized of the peptide growth factors. It acts on various elements in the nervous system and on a number of other cell types as well. It is a member of a newly discovered family of homologous growth factors, called the neurotrophins, now five in number, that supports a wide variety of neural cells. There are, in addition, a number of other peptide growth factors that are known to act on the nervous system. NGF is required for the survival and development of sympathetic and sensory neurons. It also is involved in the support of several other cell types, including specific populations of neurons in the central nervous system, the cells of the adrenal medulla, and a number of tumors as well. The action of NGF on these different cells is initiated by its binding to specific receptors. These are made up of two separate proteins, the product of the trk protooncogene and a lower-affinity site known as p75. The binding activates one or more signal transduction pathways that lead to alterations in the phosphorylation and, consequently, the function of key proteins in the cell and to changes in the expression of specific genes. These changes in protein function and in gene expression, caused by the changes in phosphorylation, are the mechanism by which NGF exerts its effects on its target cells. Much of the work leading to this concept has been done with the PC12 pheochromocytoma, a cell line derived from a tumor of the rat adrenal medulla. This clonal line continues to be one of the most informative tools available for the study of NGF and a key model for neuronal differentiation in general. In the presence of NGF, PC12 cells stop dividing, elaborate neurites, become excitable, and will synapse with appropriate muscle cells in culture. Indeed, they change from a rapidly-dividing chromaffin cell to a terminally- differentiated sympathetic neuron within a few days. The changes in phosphorylation that underlie these striking alterations in phenotype occur in virtually every compartment in the cell. Phosphorylation of NGF-stimulated calcium channels appears to regulate the calcium flux across the membrane and, in turn, the intracellular calcium levels, and these levels surely influence the survival of target neurons and may also regulate the ability of the neuron to withstand environmental insults such as occur in stroke. NGF-induced phosphorylation of the elements that control protein synthesis, such as eIF-4E, eEF-2, and S6, almost certainly alters the rate and the specificity of translation. The NGF- induced phosphorylation of specific transcription factors determines which genes are expressed. An understanding of the action of NGF will surely illuminate the control of neuronal differentiation and survival. Clinical interest in these peptide factors is intense because of the role they might play in neurodegenerative diseases.